Anti-proliferative compounds, compositions, and methods of use thereof

• US 8,268,802 B2
• Filed: 05/05/2009
• Issued: 09/18/2012
• Est. Priority Date: 12/30/2003
• Status: Active Grant

• Current Assignee: Vetdc IP LLC
• Original Assignee: Gilead Sciences Inc.
• Inventors: Cheng, Xiaoqin, Cook, Gary P., Desai, Manoj C., Doerffler, Edward, He, Gong-Xin, Kim, Choung U., Lee, William A., Rohloff, John C., Wang, Jianying, Yang, Zheng-Yu
• Primary Examiner(s): Berch, Mark
• Application Number:
  US12/436,004
• Publication Number:
  US 20090291922A1
• Time in Patent Office: 1,232 Days
• Field of Search: 514/81, 544/244
• US Class Current: 514/81
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Compounds and compositions of Formula I are described, useful as anti-proliferative agents, and in particular anti-HPV,

wherein:

• • Y^1A and Y^1B are independently Y¹;
  • R^X1 and R^X2 are independently R^X;
  • Y¹ is ═O, —O(R^X), ═S, —N(R^X), —N(O)(R^X), —N(OR^X), —N(O)(OR^X), or —N(N(R^X)(R^X));
  • R^X is independently R¹, R², R⁴, W³, or a protecting group;
  • R¹ is independently —H or alkyl of 1 to 18 carbon atoms;
  • R² is independently R³ or R⁴ wherein each R⁴ is independently substituted with 0 to 3 R³ groups or taken together at a carbon atom, two R² groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R³ groups;
  • R³ is R^3a, R^3b, R^3c or R^3d, provided that when R³ is bound to a heteroatom, then R³ is R^3c or R^3d;
  • R^3a is —H, —F, —Cl, —Br, —I, —CF₃, —CN, N₃, —NO₂, or —OR⁴;
  • R^3b is ═O, —O(R⁴), ═S, —N(R⁴), —N(O)(R⁴), —N(OR⁴), —N(O)(OR⁴), or —N(N(R⁴)(R⁴));
  • R^3c is —R⁴, —N(R⁴)(R⁴), —SR⁴, —S(O)R⁴, —S(O)₂R⁴, —S(O)(OR⁴), —S(O)₂(OR⁴), —OC(R^3b)R⁴, —OC(R^3b)OR⁴, —OC(R^3b)(N(R⁴)(R⁴)), —SC(R^3b)R⁴, —SC(R^3b)OR⁴, —SC(R^3b)(N(R⁴)(R⁴)), —N(R⁴)C(R^3b)R⁴, —N(R⁴)C(R^3b)OR⁴, —N(R⁴)C(R^3b) (N(R⁴)(R⁴)), W³ or —R⁵W³;
  • R^3d is —C(R^3b)R⁴, —C(R^3b)OR⁴, —C(R^3b)W³, —C(R^3b)OW³ or —C(R^3b)(N(R⁴)(R⁴));
  • R⁴ is —H, or an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
  • R⁵ is alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2 to 18 carbon atoms;
  • W³ is W⁴ or W⁵;
  • W⁴ is R⁶, —C(R^3b)R⁶, —C(R^3b)W⁵, —SO_M2R⁶, or —SO_M2W⁵, wherein R⁶ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;
  • W⁵ is carbocycle or heterocycle wherein W⁵ is independently substituted with 0 to 3 R² groups; and
  • M2 is 0, 1 or 2;
    and pharmaceutically acceptable salts thereof.

Claims

1. A compound of the following structure:

2. A pharmaceutical composition comprising an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

3. The pharmaceutical composition of claim 2, further comprising one or two or more therapeutically active agents selected from antiviral agents, antibiotics, antipyretics, or analgesics.

4. The pharmaceutical composition of claim 2, further comprising one or two or more therapeutically active agents selected from amantidine, rimantadine and ribavirin.